Tay-Sachs Disease
Tay-Sachs Disease Tay-Sachs is an autosomal recessive disease resulting from mutations within the gene that encodes for the α-subunit of β-hexosaminidase A (Hex A). Clinical diversity of Tay-Sachs disease arises due to the fact that over one hundred differing mutations within the Hex A gene have been noted, all of which diminish the catalytic activity of β-hexosaminidase A to a different extent1. This disease affects the central nervous system in that it leads to a loss of enzymatic activity and results in degradation of nerve cells via an accumulation of GM2 ganglioside2. Although the infant form of Tay-Sachs disease generally results in death between the ages of two and four, the adult-onset form can result in an array of neuromuscular and psychiatric symptoms. Approximately one out of every three hundred people is a carrier of a Tay-Sachs disease-causing mutation, however due to the recessive characteristic of the disease two mutated copies of the Hex A gene must be inherited to acquire it2. The prevalence of Tay-Sachs disease occurs worldwide in all ethnic groups and religions. Although it is seen widely across the spectrum, Tay-Sachs disease occurs most frequently in people of Ashkenazi Jewish ancestry as about one in every thirty-six thousand people in the general population has the disease compared to one in every thirty-six hundred people of Ashkenazi Jewish ancestry3. Genotypes and Phenotypes Although the different mutations with the Hex A gene result in a multitude of effects, it is known that some mutations (including the 1278insTATC, IVS12+1G>C and IVS9+1G>A mutations) result in a complete lack of hexosaminidase A activity. This complete loss of activity, characteristic of the infantile form of Tay-Sachs, results a severely inhibited breakdown of GM2 gangliosides and subsequent death between the ages of two and four2. The adult-onset form, however, is characterized by a more subtle mutation(s) (including the G269S mutation) that only partially inhibit the activity of hexosaminidase A . The symptoms of the adult-onset form are usually much milder than those of the infantile or juvenile-onset forms and in some cases life expectancy is not altered2. The first signs of late-onset of the disease are cerebellar or anterior motor neuron involvement that may lead to the development of psychotic episodes. As the disease progresses, speech, gait and balance problems arise alongside psychiatric disorders, proving a difficult disease to diagnose4. Amongst debilitating Hex A mutations are those (including R247W and R249W) that do not result in an alteration in the functionality of the enzyme (i.e. pseudodeficiency alleles) - although they do create positive blood tests leading to false assumptions2. John Burke's Genetics Of the four debilitating mutations mentioned, along with the two pseudodeficiency alleles, John Burke appears to be in the clear. 23andMe provided data to suggest John Burke would not have Tay-Sachs disease as neither allele for his Hex A gene contains a mutation. The high number of potential mutations, however, along with the limited availability (as 23andMe is restricted to four mutations) doesn’t allow a definitive answer to be derived from the data. References #Myerowitz R. Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. Human Mutation. 9'(3):195-208 (1997). #23andMe Tay-Sachs Disease: Your Data. https://www.23andme.com/you/journal/tay_sachs/overview/ #Freedman J. (2009). ''Tay-Sachs disease. New York: Chelsea House. Retrieved from http://site.ebrary.com/id/10326068 #Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med. '''7(2):119-123 (2005).